Schizophrenia is a disabling chronic mental disorder afflicting roughly 1% of the population. Although the cause of schizophrenia is not known, family and adoption studies have revealed that there is a significant genetic component. The genetic basis for this disorder is complex and appears to involve multiple loci. A number of genome-wide scans have identified several chromosomal regions exhibiting linkage to this disorder. Recently, neuregulin-1 (NRG1) was identified as the susceptibility gene present at the 8p locus. Despite considerable effort, no mutations that altered the amino acid sequence of NRG1 gene products were identified, and it was hypothesized that the defect may instead correspond to a change in the level of expression. Understanding NRG1 function is complicated by the existence of multiple spliced variants, which can be grouped into 3 classes (I, II, III) based upon the structure of their extracellular regions. These 3 types appear to be transcribed from 3 distinct putative promoter regions. While the current evidence favors the type II isoforms as best linked to the disorder, it appears that roles for the type I and III isoforms cannot be excluded. In this application we propose to produce distinct lines of transgenic mice that would permit the tetracycline-regulated expression of the 3 types of NRG1. The production of these mice should provide the starting point for the creation of the sophisticated mouse models required to evaluate how changes in the expression of these gene products affect neuronal migration, oligodendroglial differentiation, and neurotransmitter receptor expression, processes that NRG1 are known to influence in vitro. Accordingly, the "NRG1 mice" represent a set of genetic tools that should facilitate efforts to determine how this gene may contribute to the development of the schizophrenic phenotype, and that may ultimately permit the identification of new therapeutic strategies for this debilitating disorder. [unreadable] [unreadable]